title: Protein-bound polysaccharide-K augments the anticancer effect of fluoropyrimidine derivatives possibly by lowering dihydropyrimidine dehydrogenase expression in gastrointestinal cancers.
abstract: Protein-bound polysaccharide-K (PSK) enhances the antitumor effect of anticancer drug when used clinically in combination with such drugs. PSK is known to act by immune-mediated mechanisms; however, the relationship between PSK and metabolic enzymes of anticancer drugs is unknown. We used the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) clinically to evaluate the sensitivity of anticancer drugs. In the present study, we modified the CD-DST by adding peripheral blood mononuclear cells (PBMCs) (immuno-CD-DST) and examined the antitumor effect of PSK in combination with anticancer drugs. First, HCT116 human colon cancer cells were cultured with PSK and 5-fluorouracil (5-FU) or 5'-deoxy-5-fluorouridine (5'-DFUR) in the presence or absence of PBMCs, and the antiproliferative effects were compared. In the presence of PBMCs, PSK augmented the inhibitory effects of 5-FU and 5'-DFUR on HCT116 cell proliferation. Next, using human gastric cancer and colon cancer cell lines, the effects of PSK on mRNA expression of various metabolic enzymes of fluoropyrimidines: dihydropyrimidine dehydrogenase (DPD), thymidylate synthase, thymidine phosphorylase and orotate phosphoribosyl transferase, were examined by real-time PCR. PSK significantly enhanced DPD mRNA expression in all of the cancer cell lines tested, but not those of the other enzymes. Addition of IFN-α and TRAIL, cytokines known to inhibit DPD expression, to the cultures reduced DPD mRNA expression in the cancer cells. When PBMC samples collected from healthy volunteers were cultured with PSK, IFN-α mRNA expression increased in 3 of the 5 PBMC samples, while TRAIL mRNA expression was unchanged. The present results propose the possibility that PSK induces PBMCs to express IFN-α which inhibits DPD expression, and consequently augments the antitumor effect of 5-FU or 5'-DFUR. Immuno-CD-DST is useful for evaluating drugs with immunological mechanisms of action.
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Mekata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Murata
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sonoda
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Umeda
authors.forename: Hisanori
authors.initials: H
authors.lastname: Shiomi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Naka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
authors.forename: Takeo
authors.initials: T
authors.lastname: Edamatsu
authors.forename: Ayako
authors.initials: A
authors.lastname: Fujieda
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujioka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.forename: Tohru
authors.initials: T
authors.lastname: Tani
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D011485:Protein Binding; D013940:Thymidylate Synthase / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D011134:Polysaccharides; D005467:Floxuridine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil; C025034:doxifluridine